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Synthesis method of canagliflozin intermediate

A synthesis method and compound technology, which are applied in the field of synthesis of canagliflozin intermediates, can solve the problems of reducing production cost, complicated process and high price, and achieve the effects of reducing production cost, avoiding lattice reaction and simplifying production process.

Active Publication Date: 2018-01-09
连云港恒运药业有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0018] Using the Grignard reagent method or the Suzuki coupling method to prepare 2-(4-fluorophenyl)thiophene requires a large amount of Grignard reagents, and the process of preparing Grignard reagents in industrial production is relatively complicated.
The Suzuki coupling method requires bistriphenylphosphine palladium dichloride as a catalyst, which not only introduces heavy metals, but also 2-bromothiophene or 2-boronic acid thiophene is expensive, which is not conducive to reducing production costs

Method used

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  • Synthesis method of canagliflozin intermediate
  • Synthesis method of canagliflozin intermediate
  • Synthesis method of canagliflozin intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0037]

[0038]Add 50ml of dichloromethane into a 250ml reaction bottle, add 10.6g (0.11mol) of fluorobenzene, 14.7g (0.11mol) of anhydrous aluminum trichloride, stir the reaction solution evenly in an ice-water bath, and slowly add 10.1g of succinic anhydride g (0.1mol) of dichloromethane solution in 100ml, after the dropwise addition was completed, the temperature was slowly raised to reflux and reacted for 2 hours. After the reaction is complete, add 150ml of water, cool to 0°C, add 100ml of concentrated hydrochloric acid, stir at room temperature for 1 hour, let stand to separate layers, wash the organic layer with 150ml of saturated aqueous sodium bicarbonate solution and saturated brine successively, concentrate to dryness under reduced pressure, and perform HPLC The detection purity was 98.0%, and 16.3 g of 4-(4-fluorophenyl)-4-oxobutanoic acid was obtained by recrystallization and purification with toluene, with a yield of 83%. The purity by HPLC was 99.8%, and the ...

Embodiment 2

[0040] Add 50ml of chloroform into a 250ml reaction bottle, add 10.6g (0.11mol) of fluorobenzene, 14.7g (0.11mol) of anhydrous aluminum trichloride, stir the reaction solution evenly in an ice-water bath, slowly add 10.1g of succinic anhydride g (0.1mol) of a chloroform solution in 100ml, after the dropwise addition was completed, the temperature was slowly raised to reflux, and the reaction was carried out for 1.5 hours. After the reaction is complete, add 150ml of water, cool to 0°C, add 100ml of concentrated hydrochloric acid, stir at room temperature for 1 hour, let stand to separate layers, wash the organic layer with 150ml of saturated aqueous sodium bicarbonate solution and saturated brine successively, concentrate to dryness under reduced pressure, and perform HPLC The detection purity was 97.9%, and 15.9 g of 4-(4-fluorophenyl)-4-oxobutanoic acid was obtained by recrystallization and purification with toluene, with a yield of 81%. The purity by HPLC was 99.7%, and the...

Embodiment 3

[0042]

[0043] Add 4-(4-fluorophenyl)-4-oxobutanoic acid 19.6g (0.1mol), phosphorus pentasulfide 17.8 (0.04mol), toluene 200ml prepared by Example 1 in the microwave reactor, adjust the microwave radiation power to 160 Watts, react for 30 minutes. After the reaction was completed, toluene was recovered by distillation under reduced pressure, the residue was 200ml of ethyl acetate, 200ml of 5% aqueous sodium hydroxide solution, and after stirring, it was allowed to stand for stratification, and the organic layer was washed successively with 100ml of 5% aqueous sodium hydroxide solution, 100ml of water, and 100ml of saturated brine. After that, it was concentrated to dryness under reduced pressure to obtain 15.1 g of 2-(4-fluorophenyl)thiophene with a yield of 85% and a purity of 98.4% by HPLC.

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Abstract

The invention relates to a synthesis method of a canagliflozin intermediate. Concretely, succinyl oxide and fluorobenzene are used as starting raw materials to be prepared into the canagliflozin crucial intermediate of 2-(4-fluorophenyl)-5-[(5-halogen-2-methyl phenyl)methyl]thiophene through the steps of Friedel-Crafts acylation ring opening, thiophene ring preparation, Friedel-Crafts acylation coupling, reduction and the like. The cheap succinyl oxide is used for preparing the thiophene ring, so that the Suzuki coupling reaction and Grignard reaction are avoided; the use of heavy metal reagents of palladium and the like is avoided; the production process is simplified; the product yield and the quality are improved; the environment pollution is reduced; the production cost is reduced.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a method for synthesizing a canagliflozin intermediate. Background technique [0002] Canagliflozin, whose trade name is Invokana, is a new SGLT2 inhibitor developed by Johnson & Johnson for the treatment of type 2 diabetes. On March 29, 2013, the U.S. FDA approved Johnson & Johnson Invokana tablets (canagliflozin) for the treatment of Adult patients with type 2 diabetes; In September 2013, canagliflozin was approved by the European Medicines Agency (EMA) for the treatment of type 2 diabetes in adults. [0003] Canagliflozin is the first SGLT2 inhibitor approved by the FDA. It belongs to a new class of selective sodium-glucose co-transporter 2 (SGLT2) inhibitors. The sodium-glucose co-transporter is a glucose transporter with two Subtypes, SGLT2 is one of the subtypes, expressed near the renal tubules, and participates in the reabsorption of glucose filtered in most of the lumens. ...

Claims

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Application Information

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IPC IPC(8): C07D333/12
Inventor 张晓瑜陈刚胜张庆捷
Owner 连云港恒运药业有限公司
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